It's good to see Merck getting some momentum. If you really want to know what they are facing, stay home some day and watch the TV ads trolling for "victims" of literally dozens of discontinued drugs. Last holiday my wife - a health care practitioner - was sickened by the number and nature of them. One morning we lost count of the number of ads. She knows and prescribes the medications, and keeps up on the literature. She understands the whole risk/benefit equation - as do her patients. ALL drugs have side effects - end of story. But this special breed of trial lawyers wouldn't want the truth to get in the way of them taking what isn't theirs.

If the juries don't award the money, then maybe these people will get jobs which actually produce something.

This case is classic. Heart disease is the number 1 killer, and a 71-year-old male passing away from a heart attack is experiencing a natural and timely event. But you know those damned drug companies make a lot of money, and there's an elevated risk of a heart attack with this pain killer. So you just know there HAD to be causality... And where there's money, these ridiculous lawsuits will appear.

- Bill

Quote:

Merck Wins California Vioxx Case,Widening Edge on Trial Score Card

By ANDREW SIMONS and HEATHER WON TESORIEROAugust 3, 2006; Page A8

A California jury cleared Merck & Co. of responsibility for the heart attack of Stewart Grossberg, a 71-year-old retired construction manager who took the painkiller Vioxx for about two years.

The 12-person jury deliberated for 4½ hours before finding Merck wasn't negligent. The jury said Vioxx did have risks that were knowable but that the risks didn't present a substantial danger to users.

The verdict, in Los Angeles Superior Court, widens Merck's slight edge on the Vioxx trial score card, with the drug maker winning five trials and losing three. The Whitehouse Station, N.J., drug maker faces some 14,200 suits over Vioxx, roughly 490 of which have been filed in California. "Today's outcome demonstrates, again, why we will defend these cases on a case-by-case basis," Kenneth Frazier, Merck's general counsel, said in a statement.

Merck withdrew Vioxx from the market in September 2004 after a study known as Approve linked the drug to an increased risk of heart attacks and strokes in patients taking the drug for 18 months or longer. The New England Journal of Medicine, which published the Approve study in February 2005, recently issued a correction over the 18-month threshold, contradicting the company's position that the drug doesn't increase risk of heart attacks and strokes to people who took it for less than 18 months.

Lawyers for Merck argued that Mr. Grossberg's previous artery blockage was the cause of his heart attack. "From the beginning of time, arteries that clogged have caused heart attacks," Merck lawyer Tarek Ismail said during his closing remarks. "Literally millions of Americans have heart attacks in exactly the same way as Mr. Grossberg."

Plaintiffs' lawyer Thomas Girardi of Los Angeles-based Girardi & Keese devoted his closing remarks to arguing that Merck knew Vioxx was dangerous and that the company marketed the drug to the public anyway. He also tried to convince the jury that Vioxx was unsafe at any dose and that it was a contributing factor to Mr. Grossberg's heart attack.

Jurors weren't persuaded that Vioxx caused Mr. Grossberg's heart attack. Following the verdict, jury foreman Charles Sullenger said, "We don't feel there was a case that was ever made between Vioxx and heart attacks. The burden of proof was on the plaintiff. We didn't feel they ever met that." Another juror, Gary Adams said, "The plaintiffs focused too much on marketing." Plaintiffs' attorney Jim O'Callahan said, "There were instructions given to the jury for deliberations that we didn't agree with."

Mr. Ismail chalked the jurors' decision in favor of the drug maker up to "the cumulative effect of them getting to meet the scientists from Merck and see the care they put into it. That's what carried the day."

The second federal Vioxx trial is currently under way in U.S. District Court in New Orleans.

Seriously though, I've never understood your excessive hate of lawyers. There needs to be a counterbalance to the forces that pressure corporations to do absolutely anything for a buck. Suggesting that we leave pharmaceutical companies alone, or that we shouldn't sue; that we should just get good data so they can do the right thing by themselves, is naive. It's no different than suggesting that we shouldn't lock up murderers, we should just inform them about what they've done so that they can reform themselves. Even manslaughter carries a sentence.

I've never understood it either, Justin. So why are you accusing me of hate of lawyers, never mind "excessive hate"? Sure, I have my fun, as does every late night comic. Ever watch Jay Leno?

This is all about specific behavior and specific actions by an immoral minority within the legal community. It hardly makes sense for me to "hate lawyers" when I have two (a brother and a sister) in my immediate family and a dear friend nearby ( ) who works in a law firm.

As they say, Justin, walk a mile in my shoes. In my position in the healthcare system (as a research scientist who deals with health information), I see a lot. I see the good, the bad, and the ugly. I'm a member of a team of people who design software products that measure efficiency of practice in the healthcare system, risk for illness, and compliance to evidence-based care. I'm involved in providing tools for many aspects of improving health care.

I've also done basic science research in the past (cardiology).

My brother - an attorney - and I are like-minded on this. We had a very long conversation last September when the first Merck suits came out. Unlike what some think, lawyers come in all sizes, shapes, opinions, and political perspectives. The word my brother used when these suits started coming out was "embarassed" and "pissed." And yes, he's in the know. He once worked on the other side of the fence in the health care industry.

Justin wrote:

There needs to be a counterbalance to the forces that pressure corporations to do absolutely anything for a buck.

And what evidence do you have, Justin, that companies which produce life saving drugs will "do anything for a buck?" Inquiring minds want to know!

On the contrary, Justin, the pharmaceutical industry and the government responded to pleas from political action groups such as those who are suffering from HIV. They wanted the drug approval process to be shorter. So the FDA streamlined the process, and oops... more drugs were recalled after FDA approval because there wasn't enough data to see what it did when it reached on the order of a million people with varied health statuses. As the old adage goes, be careful what you ask for.

Personally I have no problem with the pharmaceutical industry making money. It takes a LOT of money to get a single drug from idea to market. Get someone who knows something about business and the time value of money to explain it to you some time. Those who attempt to steal from this process are destroying some of the jewels in our economy and health care system.

Justin wrote:

Suggesting that we leave pharmaceutical companies alone, or that we shouldn't sue; that we should just get good data so they can do the right thing by themselves, is naive.

With all of this, there is risk and benefit. You take risks when you approve medications in a streamlined process. You take risks and people die when you slow research down. You benefit from quick delivery to market. You benefit from a more thorough review that slows things down.

There is no perfect. The expectation with these suits is that perfect is there, we know everything that will happen before a million prescriptions are written, and nobody will suffer any side effects. That, Justin, is naive. But that's effectively the bar that a certain breed of attorney presents to a jury in these lawsuits.

Meanwhile, the plaintiff lost. Let me repeat myself, Justin. The plaintiff lost. The majority of juries are shown now to agree with a position I took a year ago. And why? Let's look at what they did.

They discovered a drug that causes a slight increase in the risk of a cardiac event.

Cardiac events are the number 1 killer. It's probably what you will die of, Justin. It's probably what I will die of.

They trolled for people with cardiac events who took the drug, and now are implying causality.

Anyone who understands the numbers, the risks, and the logic knows what utter bullschit their cases are. There IS no proof that the drug caused any one heart attack. There isn't even proof that Vioxx caused a significant percentage of all cardiac events in people who took the pain reliever. And yet they are trying to convince juries of just that.

Merck DID do the right thing. When the evidence became clear, they removed the drug from the market.

FWIW Celebrex - another COX II inhibitor pain reliever - is still out there on the market. But the warnings are now presented clearly to the patients - NOW THAT WE KNOW THE RISKS.

Justin wrote:

It's no different than suggesting that we shouldn't lock up murderers, we should just inform them about what they've done so that they can reform themselves. Even manslaughter carries a sentence.

This makes no sense.

Mary wrote:

I think those ads are on the same channels that show the ads extolling the virtues of the latest super drugs that "you should ask your doctor about" - a little sick of seeing those day after day too.

I'm more than a little tired of pharmaceutical companies trolling the common man/woman.....

I agree 100%, Mary. When I look at the top 10 list of drugs (by dollar) at any one point in time, you're basically looking at the list of all drugs you see on TeeVee. Direct-to-consumer advertising isn't something that most people in the medical community are fond of.

I don't know what to say or what to do about it. And unfortunately this too is driven by the almighty dollar. Obviously the advertising works.

Back in the day, the drug companies would advertise instead to the physicians. But this too can get out of hand, and still does to some extent. Every doctor knows of the tall, leggy drug reps with short skirts who come in with free lunches to "educate" the physicians about new drugs. And of course there are those free sporting events, trips to vacation spots to get more "education", etc. Frankly the AMA can and should do more about this, but they don't.

I personally refuse any such perks. The wife gets all these tickets to wonderful events for her and the family, and she knows that she has to tell the drug rep that hubby won't go.

Follow the dollar in all this bad behavior, and go from there. But by all means, don't let the parasites get any of it. There are better ways to improve the health care system. Redistribution of wealth to immoral opportunists isn't a solution.

1) Vioxx users have an increased risk of heart attack, including fatal heart attack, compared with users of other medications.

2) Merck had data about cardiovascular risks that it failed to inform the New England Journal of Medicine about before the key article went to print.

3) Merck didn't disseminate that data to physicians weighing the risks and benefits of this drug with their patients as fast as it could have, either.

4) Merck was making billions on Vioxx.

If you want to establish the veracity of 1-3, please see the Expression of Concern written by the editorial staff of the NEJM in response to Merck's actions. If you want to find proof that drug companies will do anything for a buck, well, I have none, but there's some pretty good circumstantial evidence. Consider whether there might be a profit motive linking 1-3 and 4, for example.

a) Or heck, remember eflornithine? That's the "resurrection drug" that revives east africans with sleeping sickness. They don't pay, so american companies stopped making it, ending it's availability.

b)We've also had recent shortages of penicillin because that wasn't profitable either, if you want something less esoteric and closer to home.

c) Or remember seldane? My mom wanted me to take it even though my allergies never bothered me. It causes potentially lethal arrythmias. The maker tried to squeeze every cent out of it rather than more quickly moving to what it breaks down to in the body, the active, harmless substance we now call Allegra.

d) Companies deliberately release XR formulations near the end of one patent to extend their market share, rather than upfront, although they could.

e) They consistently try to switch patients from effective product one to effective product 2 when patent on #1 runs out, again, to keep patients on patented meds. Examples: prilosec to nexxium, neurontin to lyrica.

f) They make up absurd unecessary products, like Xanax XR; Xanax is a crummy drug that is reinforcing, hence addictive, and inferior to the similar klonopin or valium; all xanax XR does is mimic those two drugs--for many times the price.

g) They price drugs in the manner which will net them the most cash, not do the most good, and advertising and production have nothing to do with it. For example, zofran and epogen are both extravagantly expensive because they shorten the stays of cancer patients, making it barely more efficient to use them than not for the cancer patients and difficult to use them in, say, the ever expanding list of patients with chronic renal failure who can often barely afford them.

h) They try to find ways to promote the use of new expensive drugs for things that older cheap drugs might do better--that's why we just saw the makers of candesartan fund a trial on treating prehypertension, rather than the one clinicians would design, using hctz or lisinopril, well known and generic medications that no one wants to promote because its the right, but not profitable, thing to do.

i) Drug companies try to expand the definitions of illness so they can sell more drugs, for example, claiming we all need modafinil because being tired when we're overworked is an illness, or claiming that 1 in 8 of us have social anxiety disorder, aka, being halfway shy around a girl.

j) They delay studies to seek indications late in a drug's life and rename it to keep selling it under a new brand name once the parent drug is generic, which is how we came to use expensive Sarafem (fluoxetine) to treat PMS in some women and expensive Prozac Weekly (fluoxetine) instead of generic fluoxetine once Prozac (fluoxetine) went off patent.

k) they pay their reps to lie (omission or commission) to physicians in ways that can harm individual patients or communities. Some told me to use azithromycin for bronchitis; it doesn't work, that is proven 100%, and it would waste money, cause side effects, and lead to drug resistance, harming us all.

l) they fight for their drug rather than the best for a patient, for example, gatifloxacin is still on the market even though its the same as moxifloxacin which doesn't case the diabetes that gati does; telithromycin is pushing to be used in all asthmatics even though it appears to cause fatal liver failure, when azithromycin does not.

m) they skew risks, benefits, and indications with misleading direct to consumer ads.

These are just examples I've observed. I haven't lifted a finger to look for these examples.

Drug companies are out to make money, not necessarily "do the right thing." Frequently when they do the right thing it's to make money, anyway. They don't sit down thinking about what drug might be the most useful for society, but rather which might make more money. This doesn't make them bad, this makes them snakes. Snakes get hungry, and then they eat, and morality doesn't come into it. Lawyers, at least some of them, are also snakes. And snakes can expect other snakes to bite if they get the chance, which means Merck should have expected to be fighting lawsuits because it didn't do for all its customers what its executives certainly did for family and friends--give the truth, the whole truth, and nothing bu the truth

So Merck can answer for its errors. Vioxx killed a percentage of patients, including some with, you guessed it, preexisting coronary artery disease. Vioxx makes platelets stickier, and as docs have come to understand in recent years, heart attacks are more of a medical or molecular problem than a mechanical problem. What causes the acute reduction in blood flow isn't the wad of cholesterol goo, but an inflammatory response that leads to the development of a clot. Platelets get activated by a ruptured plaque and release chemicals that clot the blood. As it turns out, Vioxx makes platelets stickier; the same chemical processes that regulate inflammation in pain regulate the production of stomach acid and paltelet activation, and Vioxx leans toward activating platelets. The result is that if x percent of 100 people not on Vioxx would have had a heart attack over 2 years, x + y percent have one if they're on Vioxx. Y isn't big for individuals but in a nation where heart disease is common, its tens of thousands of people. So, again, Merck made a cash based decision that led to patient deaths. In this, its not unlike a tobacco company. I don't blame tobacco companies for existing. Well, I do. But mandatory for any fully ethical company is complete honesty.

I can't agree with you more that the forum in which it is making amends is profoundly stupid. It doesn't make sense to try to figure out whether Vioxx killed a particular patient, because that's impossible, and its stupid to stand up in court and say Vioxx killed Fred Smith when the odds are it didn't.

Try to think of it as a system with limited options. At UVA, you only have two choices for punishment if a student lies, cheats, or steals: innocent, or banned from the university forever. As a result people who steal are let off, or not reported; others could get kicked out of UVa forever for a minor theft. Think of the lawsuits being the expulsion. It's extreme, its excessive, but (they were greedy, angry, litigious patients or lawyers AND) they didn't want to do nothing and let Merck police itself. Is that sooooo crazy?

Absolutely. The #1 job of a publicly held company is to make money for the shareholders. Period. When a company does not do this the board of directors' duty is to fire the CEO and hire one to fix the problem and make money for the shareholders. There is nothing altruistic in it. Merck is not in business to make drugs, it is in business to make money.

The positive side is that these companies do come up with some really great products to extend lives or make your whites clothes whiter and brighter. God bless capitalism.

Quote:

harmless substance we now call Allegra

Not harmless to me. It makes me quite ill. I tried zrtec this spring and it also causes more side effects than I care for. I stick to Benedryl and just take care to not use it if I am driving or operating a dangerous machine.

As for lawyers, my hopes of making enough $$ via my force continuum hobbies to stay semi retired were dashed when the insurance required would make any such business unprofitable. Plus my existing carrier theatened to drop me... too much liability they said.

And, part of this year's $$ run-up in gasoline prices is because the refiners switched from a government mandated oxygenater - MTBE - to ethanol ahead of schedule and before the infrastructure could support the demand. Why did they suddenly switch? It seems the government mandated MTBE has environmental issues but the govt refused to block law suits created over the additive they mandated. All the risk is on the oil companies, and they would have and may still be sued by Californinia, among others, a state that also mandated MTBE. Thank big brother and the big law for a percentage of this year's gas price increase!

Ian: What is your malpractice insurance costing you? I'd trust you to work on me insured or not. In Virginia rural regions have almost no OB services because small town docs cannot afford the liability insurance.

This whole capitalism thing in America was started way back around the time of the founding of the first permanent colony in North America - Jamestown in 1607. To get the colonists moving the then leader of the colony - might have been Rolfe or Smith - parceled up the common land and told everyone they were basically on their own, but could keep all they produced as well as any profits they made via trade of the surpluses. Voila, Jamestown and Virginia flourished.

Profit is a good thing. It motivates almost everyone to be productive. Litigation is counter productive and produces no wealth.

Merck had data about cardiovascular risks that it failed to inform the New England Journal of Medicine about before the key article went to print.

I challenge you, Ian, to convince me and the world that these data they had were statistically irrefutable. I think you'll find they weren't.

The problem here is that Vioxx causes a slight increase in the risk of a coronary event - and I mean SLIGHT. The risk is so small that it was missed in other drugs in some cases for decades. Now we know that even naproxen is associated with some of the very same risks. So is Celebrex. So is bextra. But Merck is where the money is, so...

I build models to predict risk of future health care events and heath care resource consumption all the time, Ian. I use the records of anywhere from several million to several tens of millions of people over years of time. And even there, you can get some very odd false positive and false negative results that only careful review will clear. Some things are obvious, such as being obese or smoking is bad for you. And even those things take time to understand completely. Some things such as the use of a painkiller in a population already about to die of a heart attack in the near future are not so obvious.

20/20 hindsight is a wonderful thing, isn't it? Perhaps we should use that to tell John Edwards to give all the money back he stole from OBs because he convinced juries that they caused moms to deliver CP babies. Never mind that the evidence now shows otherwise. But that money will be returned when monkeys start leaping from your butt (comedic movie scenes aside... ).

Ian wrote:

Drug companies are out to make money, not necessarily "do the right thing." Frequently when they do the right thing it's to make money, anyway. They don't sit down thinking about what drug might be the most useful for society, but rather which might make more money.

This is a patently false assertion, Ian.

Making the customer happy is good business. Please read a basic book on six sigma. Refer to the chapters entitled "voice of the customer." As they say, quality drives cost. And cost drives profit.

Making money can be a win-win situation.

Oh, and did I mention that companies like Merck are owned by shareholders? If you have a retirement plan, put money in an interest-bearing account, own a mutual fund, or live in an area where the government attempts to generate revenue from its assets, then these 14,200 lawsuits in the queue are a tax on YOUR life. This ultimately is money taken out of YOUR pocket, and going to immoral professionals who will do it again in a heartbeat. These people are not stupid. They understand that the proof is not there, nor is the expectation that the painkiller in question likely caused what they are claiming.

Ian wrote:

So Merck can answer for its errors. Vioxx killed a percentage of patients, including some with, you guessed it, preexisting coronary artery disease.

And Vioxx also relieved pain. And pain is associated with both morbidity and even mortality. So for every QALY (quality-adjusted life year) on the debit end from sticky platelets, we have way more than enough on the credit side from pain relief. I'm confident that we can state they are in the black on QALYs, and this, Dr. Ian, is the medically-accepted standard for improving our lot in life with a therapy.

It's a risk/benefit situation, Ian. If you're not willing to take risks in life, you'd better stay at home. God forbid you operate a motor vehicle. Should we start class action lawsuits against GM now? Susie Smith would still be alive today if she hadn't driven her little sports car to work.

Give me a friggin break!

Ian wrote:

So Merck can answer for its errors. Vioxx killed a percentage of patients, including some with, you guessed it, preexisting coronary artery disease. Vioxx makes platelets stickier, and as docs have come to understand in recent years, heart attacks are more of a medical or molecular problem than a mechanical problem.

You just contradicted yourself, Ian.

You're arguing with the wrong guy. I spent 3 years in cadiology research creating and studying ischemia, occlusions, and myocardial infarctions in the lab. I've got the publications to prove it if you ever want to dig into the literature. (Circulation Research, Circulation, JCI, etc.)

We've already established that Vioxx increases the risk of a coronary event. We haven't and never will establish that Vioxx is the primary cause of ANY of these events. You cannot have the event without a lifetime of bad living and/or genes and or plain-old old age setting the stage for you being on the precipice.

You can give me Vioxx all day long and my platelets will never find a place to create mischief. And you'll have hundreds if not thousands of Vioxx users take the painkiller and die of a coronary event NOT due to the painkiller before you find one who - if (s)he had not taken the medication - would not have had the attack that day.

Ian wrote:

Try to think of it as a system with limited options. At UVA, you only have two choices for punishment if a student lies, cheats, or steals: innocent, or banned from the university forever. As a result people who steal are let off, or not reported; others could get kicked out of UVa forever for a minor theft. Think of the lawsuits being the expulsion. It's extreme, its excessive, but (they were greedy, angry, litigious patients or lawyers AND) they didn't want to do nothing and let Merck police itself. Is that sooooo crazy?

YES! End of story.

And fortunately that's why we have juries - including for honor trials at UVa. And if you'll re-read (?) the article I posted, it's now becoming apparent that my point of view is the majority point of view when all the evidence is put on the table.

Meanwhile, does Merck get restitution for all these inappropriate suits? Do I get restitution for the money that the ambulance chasers are taking out of my retirement account when Merck has to address this nonsense? I'm a "little guy" too in this scenario, as is every other person in middle American trying to retire.

"I challenge you, Ian, to convince me and the world that these data they had were statistically irrefutable. I think you'll find they weren't."

It's not Merck's right to decide what information they have about their drug's potential (in this case, occasionally lethal) side effects that they will release to medical journals and to the public. It's their job. And before *I* prescribe or take a medication, I want to know what the executives at that company are concerned about. There's a reason they didn't release this data. It was going to cost them. But there's a reason the patients and doctors out there deserved to have access to it, and that's where Merck....

DID THE WRONG THING.

You want to dispute this? You can overrule the New England Journal of Medicine then. They're convinced. And you're not about to tell me you know your cardiology and medical ethics and statistics better than they do--or are you?

"This is a patently false assertion [that drug compnies are out to make money], Ian."

Oh really? Why did Rich agree with me? Read his post. **I didn't say it was wrong**. I didn't say that it's not sound financial planning to come up with wonderful drugs to better mankind and to keep customers happy. It often is. But the #1 job is profit motive: drug companies, like tobacco companies, have self interest first when they consider their sales. Do I need to complete my alphabet of examples of profit first, ideal medicine second thinking to convince you?

"Please read a basic book on six sigma."

Thanks, I will; this is something I'm utterly stupid about since it never seems to come up at any of my several quality improvement projects or safety committees that constitute a large fraction of my job.

"And Vioxx also relieved pain. And pain is associated with both morbidity and even mortality . So for every QALY (quality-adjusted life year) on the debit end from sticky platelets, we have way more than enough on the credit side from pain relief. I'm confident that we can state they are in the black on QALYs, and this, Dr. Ian, is the medically-accepted standard for improving our lot in life with a therapy."

Here's where we differ: you look at processes from a distance, I meet 8-18 patients every day. A drug company cannot decide, or have you decide, that a drug did net more good than harm, and then conceal some of those harms from the public. This is because my patients have a right to informed consent, not a statistical analysis on whether merck caused more good than harm. These are people, not numbers. That's why we can't sacrifice a person in a vegetative state to save 10 people with organ transplants.

"Should we start class action lawsuits against GM now?"

I think we should have a nonlawsuit option to pursue, just like you do. However, if a class action lawsuit is my only recourse against GM, **AND** GM fails to notify me that some of their cars are more prone to explode, and then my relative dies in an inferno in one, then YES, I absolutely will sue them for their unethical behavior because I will not be comforted by their net benefit to society or their responsibility to stakeholders because neither is a license for bad behavior.

"You just contradicted yourself, Ian."

No, I didn't. If Vioxx causes more people to die of heart attacks than placebo, it does not matter ethically or medically if it was the "primary cause" or not. Merck does not get out of jail free just because a patient was old, had a hereditary high cholesterol or blood pressure, or made poor lifestyle changes, just like I would not get out of jail free if I yelled "Fire" in a theatre for fun and an old smoker with prior heart disease died of a coronary in the stampede. That's a preposterous assertion. What I said was and is true: people die of acute clots, and those acute clots are in large part dependent on platelet activity (hence the well known effectiveness of aspirin, glycoprotein 2b/3a inhibitors and clopidogrel, antiplatelet agents used in treating and/or preventing heart attack), and Vioxx moves platelet behavior in the other direction, and that induces some people to have heart attacks they otherwise would not have. And before you propose that only the elderly and "lifetime bad living" set are vulnerable to heart attack, consider that the majority of Americans eat an unhealthy diet, don't exercise enough, or eventually get heart disease anyway. That's the context in which Vioxx was used.

"And fortunately that's why we have juries - including for honor trials at UVa."

So what you're saying is these disputes should be settled in front of a jury? I'm sure Gene is thrilled. I think that there's a better way because no science can tell us if Joe smith would or would not have died if he hadn't taken Vioxx--and it doesn't matter, anyway, because there's no way to have known before he took it either. What matters is that Merck, through willful omission, prevented people from full access to information they had the right to use to make their decision about vioxx, and some of them died.

_________________--Ian

Last edited by IJ on Sun Aug 06, 2006 7:38 pm, edited 1 time in total.

A composite cardiovascular end point of death from cardiovascular causes, myocardial infarction, stroke, or heart failure was reached in 7 of 679 patients in the placebo group (1.0 percent), as compared with 16 of 685 patients receiving 200 mg of celecoxib twice daily (2.3 percent; hazard ratio, 2.3; 95 percent confidence interval, 0.9 to 5.5) and with 23 of 671 patients receiving 400 mg of celecoxib twice daily (3.4 percent; hazard ratio, 3.4; 95 percent confidence interval, 1.4 to 7.. Similar trends were observed for other composite end points. On the basis of these observations, the data and safety monitoring board recommended early discontinuation of the study drug.

Conclusions Celecoxib use was associated with a dose-related increase in the composite end point of death from cardiovascular causes, myocardial infarction, stroke, or heart failure. In light of recent reports of cardiovascular harm associated with treatment with other agents in this class, these data provide further evidence that the use of COX-2 inhibitors may increase the risk of serious cardiovascular events.

A total of 46 patients in the rofecoxib group had a confirmed thrombotic event during 3059 patient-years of follow-up (1.50 events per 100 patient-years), as compared with 26 patients in the placebo group during 3327 patient-years of follow-up (0.78 event per 100 patient-years); the corresponding relative risk was 1.92 (95 percent confidence interval, 1.19 to 3.11; P=0.008). The increased relative risk became apparent after 18 months of treatment; during the first 18 months, the event rates were similar in the two groups. The results primarily reflect a greater number of myocardial infarctions and ischemic cerebrovascular events in the rofecoxib group. There was earlier separation (at approximately five months) between groups in the incidence of nonadjudicated investigator-reported congestive heart failure, pulmonary edema, or cardiac failure (hazard ratio for the comparison of the rofecoxib group with the placebo group, 4.61; 95 percent confidence interval, 1.50 to 18.83). Overall and cardiovascular mortality was similar in the two groups. Correction issued later: "In a post hoc assessment, visual inspection of Figure 2 suggested that the Kaplan–Meier curves separated 18 months after randomization. However, the results of an overall test of the proportional-hazards assumption for the entire 36-month observation period did not reach statistical significance (P=0.07)."

Nissen (letter): Volume 355:203-205 July 13, 2006 Number 2
The original article included a post hoc hypothesis that curves for confirmed thrombotic events would not begin to diverge until after 18 months of exposure to rofecoxib. However, all intention-to-treat analyses in the newly released report show that the event curves begin to diverge much earlier, generally within four to six months. The most useful Kaplan–Meier curves, involving intention-to-treat analysis of the APTC end point, show divergence after only three months of exposure to rofecoxib (Figure 1). Figure 2 shows the intention-to-treat analysis for confirmed thrombotic cardiovascular events. The Adenoma Prevention with Celecoxib (APC) study, a trial otherwise similar in design, reported data in which the intention-to-treat approach was used, with no censoring of delayed events.3

Note section on thrombogenicity of vioxx and theory that naproxen was protective.

Okie, S. What Ails the FDA? Volume 352:1063-1066 March 17, 2005 Number 11
"Testifying before a spellbound audience in a Senate hearing room this past November, scientist and whistle-blower David J. Graham charged that his employer, the Food and Drug Administration (FDA), is incapable of protecting the public from dangerous prescription drugs. Graham, an epidemiologist who monitors drug safety, conducted a study that confirmed an increase in the risk of myocardial infarction among users of rofecoxib (Vioxx), Merck's blockbuster antiinflammatory medicine. When he informed his supervisors about his findings last summer, he said, they pressured him to change his conclusions because they were inconsistent with the FDA's position on the drug's safety. A few weeks later, Merck withdrew Vioxx from the market in the face of studies suggesting that it had contributed to tens of thousands of heart attacks.

"Vioxx is a terrible tragedy and a profound regulatory failure," Graham told the Senate Finance Committee.

Note: "Coincident with the approval of rofecoxib and celecoxib in 1999, my colleagues and I reported that both drugs suppressed the formation of prostaglandin I2 in healthy volunteers.2 Prostaglandin I2 had previously been shown to be the predominant cyclooxygenase product in endothelium, inhibiting platelet aggregation, causing vasodilatation, and preventing the proliferation of vascular smooth-muscle cells in vitro. However, it was assumed that prostaglandin I2 was derived mainly from COX-1, the only cyclooxygenase species expressed constitutively in endothelial cells. This assumption later proved incorrect, since studies in mice and humans showed that COX-2 was the dominant source. The individual cardiovascular effects of prostaglandin I2 in vitro contrast with those of thromboxane A2, the major COX-1 product of platelets, which causes platelet aggregation, vasoconstriction, and vascular proliferation.

Whereas aspirin and traditional NSAIDs inhibit both thromboxane A2 and prostaglandin I2, the coxibs leave thromboxane A2 generation unaffected, reflecting the absence of COX-2 in platelets. Increasing laminar shear stress in vitro increases the expression of the gene for COX-2, leading our group to suggest that COX-2 might be hemodynamically induced in endothelial cells in vivo. If so, suppression of the COX-2–dependent formation of prostaglandin I2 by the coxibs might predispose patients to myocardial infarction or thrombotic stroke.

Thus, a single mechanism, depression of prostaglandin I2 formation, might be expected to elevate blood pressure, accelerate atherogenesis, and predispose patients receiving coxibs to an exaggerated thrombotic response to the rupture of an atherosclerotic plaque. The higher a patient's intrinsic risk of cardiovascular disease, the more likely it would be that such a hazard would manifest itself rapidly in the form of a clinical event. "

Oberholzer; Merck's REcall of Rofecoxib
When Merck announced the voluntary withdrawal of its acute-pain medication, rofecoxib (Vioxx), on September 30, 2004, its stock price collapsed, wiping out more than a quarter of the company's market value in a single day. A second blow came on November 1, when an article in the Wall Street Journal suggested that Merck had known about elevated risks of heart attack and stroke for years and had tried to intimidate scientists who questioned the safety of rofecoxib. On that day, Merck's stock price fell by another 10 percent. The recall came as a shock not only to patients and their physicians; the debacle was also terrible news for those awaiting new medical therapies, because the dramatic financial consequences of withdrawing rofecoxib might well hamper the ability of a major pharmaceutical company to invest in new drugs that could help patients in the future.

And here's the conclusion, of a sort:
Expression of Concern Reaffirmed

Gregory D. Curfman, M.D., Stephen Morrissey, Ph.D., and Jeffrey M. Drazen, M.D. "The information we have indicates that the VIGOR article, because it did not contain relevant safety data available to the authors more than four months before publication, did not accurately reflect the potential for serious cardiovascular toxicity with rofecoxib. We therefore reaffirm our expression of concern. "
http://content.nejm.org/cgi/content/ful ... type=HWCIT

It's not Merck's right to decide what information they have about their drug's potential (in this case, occasionally lethal) side effects that they will release to medical journals and to the public.

Oh yes it is. Ask ANY researcher in academia or industry what does or does not get released in the literaturer. Negative findings aren't sexy, so never make it to the literature. Findings that don't support your pet theory don't make it to the literature, nor are they likely to make it past the peer-review process if you try to submit such a publication.

Do you publish, Ian? If you did, you would know that.

A researcher in academia or industry has every right not to release information - particularly and especially if it is inconclusive.

It wasn't the study you cite that turned the corner, Ian. It was the Approve study. Only after the fact - with 20/20 hindsight - did the release of old information that was consistent with that study make sense.

Let's put this in context, Ian. Why didn't the makers of Celebrex report the same findings? (Hint: the evidence wasn't yet there.) Why didn't the makers of Bextra do the same? (Hint: the evidence wasn't yet there.) Naproxen has been around for 3 decades. Why are we finding out JUST NOW that this medication similarly causes the same increase in risk?

And what about ibuprofen, for Christ's sake? Do you know how many premenstral women, aging athletes, and generally aching people have put themselves at risk of side effects that we're just now finding out about?

Should we ban the use of knives in the kitchen? Should we ban aspirin? Should we sue the makers? Both of these have caused orders of magnitude more deaths WHEN USED AS DIRECTED. We didn't even know how aspirin worked until recently, much less what all the dangerous side effects are.

Ian wrote:

You want to dispute this? You can overrule the New England Journal of Medicine then. They're convinced.

After the fact. With 20/20 hindsight. Meanwhile, talk to the review board of NEJM about what articles they do and don't allow to get published, and what they demand of people who do publish.

Talk to them about how naproxen was out there for decades without them getting information that showed the exact same side effects. Where were the people in the ivory towers for those 3 decades? Where was NIH when it came time to award grants-in-aid?

Ian wrote:

"This is a patently false assertion [that drug compnies are out to make money], Ian."

No, Ian. DO NOT DO WHAT YOU JUST DID! Literally putting words in my mouth that I did not type (nor did I imply) is just plain wrong.

This is the record.

Bill Glasheen wrote:

Ian wrote:

Drug companies are out to make money, not necessarily "do the right thing." Frequently when they do the right thing it's to make money, anyway. They don't sit down thinking about what drug might be the most useful for society, but rather which might make more money.

This is a patently false assertion, Ian.

Making the customer happy is good business. Please read a basic book on six sigma. Refer to the chapters entitled "voice of the customer." As they say, quality drives cost. And cost drives profit.

Your a smart guy (understatement of the year), so I can't take you as being unintelligent. Maybe you were careless, or uninformed on the subject. Please read a book on six sigma so you'll get on board with my argument.

Ian wrote:

Here's where we differ: you look at processes from a distance, I meet 8-18 patients every day. A drug company cannot decide, or have you decide, that a drug did net more good than harm, and then conceal some of those harms from the public.

Here's where our arguments differ.

I am asserting that NOBODY knew these risks for certain until the Approve study was published. I am asserting that the same risks existed for other painkillers on the market far longer (and via the exact same biochemical mechanisms) and nobody caught it. Suddenly Merck is the bad guy - because the pockets are deep, the drug is new, the news was sexy, and somebody who files suits seeking class action status for a living started cranking them out.

Ian wrote:

This is because my patients have a right to informed consent, not a statistical analysis on whether merck caused more good than harm. These are people, not numbers. That's why we can't sacrifice a person in a vegetative state to save 10 people with organ transplants.

And here is where I believe I have a right to "lecture" you, Ian.

You have no business giving patients a new drug without warning them that it is new and so little data exists to understand all the many side effects and risks. My spouse does this as a matter of course, Ian. She refuses to give out the free samples to her new patients when something which likely will get the job done is available at a fraction of the long-term cost.

It is your responsibility to understand this big picture, Dr. Ian. You've been around long enough to see how many new drugs come on to and off of the market. And with more and more drugs "out there", there is a greater and greater chance of drug-drug interaction. The chance of that goes up exponentially with each new drug that enters the the pool of medications that make it into the pool of available therapies. Please don't shirk this responsibility, or pretend you can for the sake of this argument when I know you and know you wouldn't.

FWIW, we're working on more and more software to help you out in this matter... (No sales were made in the making of this claim. )

Ian wrote:

Bill wrote:

You just contradicted yourself, Ian.

No, I didn't.

Yes you did.

You claimed

Ian wrote:

heart attacks are more of a medical or molecular problem than a mechanical problem.

Then you wrote

Ian wrote:

Vioxx killed a percentage of patients, including some with, you guessed it, preexisting coronary artery disease.

There's your mechanical problem. And you can't get the platelets to stick without it. Heart attacks start with the mechanic problems (the stenosis, caused by the buildup of plaque).

And you can hardly compare someone FALSELY yelling "Fire!" in a movie theater causing a heart attack in someone ready for the event to a patient taking Vioxx.

Here's the proper comparison. There is really and truly a fire in the theater. So you you yell "Fire!" You save some lives, but some poor man with a critical stenosis dies from the fright. Does the family have a right to sue? EVERYONE has a right to sue, but nobody's going to convict.

Patients took (and still take) COX II inhibitors to relieve pain and reduce the risk of bleeding. That's a known side effect of NSAIDs, and it does indeed kill people. But in a population of people who avoided bleeding events, some got sticky platelets which found a critical stenosis.

THERE IS NO FREE LUNCH! THERE ARE NO DRUGS WITHOUT SIDE EFFECTS OR RISKS.

And yes, we don't know all the risks, nor do we necessarily understand them when they first start rearing their ugly heads.

It was a long time after men started dropping like flies in San Francisco bath houses in the latter 1970s before we understood what the heck was going on. And it had been going on for decades!

Ian wrote:

So what you're saying is these disputes should be settled in front of a jury? I'm sure Gene is thrilled.

I'm saying "Fair is fair." 14,200 lawsuits for an unjust cause? Let's start the class action lawsuits against these ambulance chasers. Our retirement accounts are being raided. Let's get restitution!

Funny you should use this as an example. The nanny state called Great Britain has a move afoot to ban household knives with points and longer than necessary... 4 inches maybe. This is laughable.

Quote:

Patients took (and still take) COX II inhibitors to relieve pain and reduce the risk of bleeding.

That would be me. With GERD even Tylenol causes me some problems. Celebrex is a perfect fit and is superior to anything I have ever tried. My dosage is low - 100mg - and the family doc makes me have a blood test periodically before renewing an Rx so the small risk, which I accept, is worth it.

When the news about heart attacks and strokes came out a few years ago I stopped taking Celebrex completely. None of the over the counter nsaids did the trick. In an effort to keep me off Celebrex BCBS offered me high dose Tylanol at basically no cost. However, the risk of damaging my liver increases dramatically with high doses of Tylenol... a much higher risk of serious harm than what I see associated with Celebrex. Personally I believe it is not a concern for my health as much as as it is for the bottom line. Anthem eventually denied me access to Celebrex so I just buy it from Drugstore .com with an appropriate Rx.

Before the results of the APPROVe study were released, the scientificevidence of gastrointestinal benefit from coxibs in the VIGOR and TARGET trials appeared to outweigh the evidence of cardiovascular risk. The FDA pursued a cautious policy, labeling celecoxib and rofecoxib in ways that reflected the outcomes of the CLASS and VIGOR trials. However, the APPROVe study has shifted the burden of proof. We now have clearevidence of an increase in cardiovascular risk that revealed itself in a manner consistent with a mechanistic explanation that extends to all the coxibs. It seems to be time for the FDA urgently to adjust its guidance to patients and doctors to reflect this new reality. Only the FDA can provide unbiased and informed guidance; it has a role to play beyond watchful waiting. In the absence of such guidance, what should physicians and their patients do? Selective inhibitors of COX-2 remain a rational choice for patients at a low cardiovascular risk who have had serious gastrointestinal events, especially while taking traditional NSAIDs. It would also seem prudent to avoid coxibs in patients who have cardiovascular disease or who are at risk for it.

The rofecoxib story also reflects poorly on the process that leads to drugapproval. The rational basis for addressing the cardiovascular effects of these drugs has been clear for the past five years, yet even the most fundamental questions have not been addressed directly. Much informationcould have been derived from careful mechanistic studies in small numbersof patients and volunteers. However, drug companies are driven by thecurrent requirements for drug approval to design studies such as TARGET.This most expensive and largest of the outcome studies involved exposingmore than 18,000 patients to lumiracoxib for a year. It laid the foundationfor the approval of another coxib, but it failed to address importantquestions about cardiovascular risk raised by the VIGOR trial and bymechanistic and epidemiologic studies.

Merck did the right thing after the APPROVe study results came out. Before
then there was no conclusive information. Furthermore, NEJM in this
editorial is identifying a PROCESS problem. All the trial attorneys in the
world won't fix that.

READ SIX SIGMA!!! It isn't bad people or bad companies or bad
shareholders. It's a bad process that the government created, and one
they need to fix. It was a process that was supposed to address a consumer
request to speed the delivery of life-saving drugs to market. But as they
say, no good deed goes unpunished.

Furthermore, the wrong party here is getting "punished." But that's a classic
case of Sutton's law in action. It isn't about who is right or who is wrong.

"Merck did the right thing after the APPROVe study results came out. Before then there was no conclusive information. Furthermore, NEJM in this
editorial is identifying a PROCESS problem. All the trial attorneys in the
world won't fix that. "

Actually, No. Merck suppressed some data, such that what was published wasn't accurate. Read the NEJM's expression of concern. Just because there are flaws with the drug approval process which must be fixed, it does not mean that merck must be or is blameless. Merck suppressed data about bad outcomes! That violates the golden rule; you can't do that in court; according to JC, you're not supposed to do it ever. It's wrong. It's also disturbing it was done for money. I would not have done it. Merck erred.

I'm not saying they should get slaughtered in the courts--that's something else. There is a difference between advocating responsibility and advocating the current legal process.

"READ SIX SIGMA!!! It isn't bad people or bad companies or bad
shareholders. It's a bad process..."

Bill. Again. This is my job. It is a key component of the hospitalist movement, especially at academic medical centers, which is where I work. I'm aware.

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